Periodic propagating waves coordinate RhoGTPase network dynamics at the leading and trailing edges during cell migration

Abstract

Migrating cells need to coordinate distinct leading and trailing edge dynamics but the underlying mechanisms are unclear. Here, we combine experiments and mathematical modeling to elaborate the minimal autonomous biochemical machinery necessary and sufficient for this dynamic coordination and cell movement. RhoA activates Rac1 via DIA and inhibits Rac1 via ROCK, while Rac1 inhibits RhoA through PAK. Our data suggest that in motile, polarized cells, RhoA–ROCK interactions prevail at the rear, whereas RhoA-DIA interactions dominate at the front where Rac1/Rho oscillations drive protrusions and retractions. At the rear, high RhoA and low Rac1 activities are maintained until a wave of oscillatory GTPase activities from the cell front reaches the rear, inducing transient GTPase oscillations and RhoA activity spikes. After the rear retracts, the initial GTPase pattern resumes. Our findings show how periodic, propagating GTPase waves coordinate distinct GTPase patterns at the leading and trailing edge dynamics in moving cells.

Single-component optogenetic tools for inducible RhoA GTPase signaling

“…The cell centroid displacement vector was highly preferential toward the leading edge (Figure 2e-f), meaning that the cytoskeletal retraction was predominately at the trailing edge and along the polarization axis upon stimulating the whole cell. This trend suggests that the tensile asymmetry introduced by the underlying cell polarization drives the cytoskeletal morphology changes upon optogenetic activation of stress fiber formation, and it is consistent with the fact that RhoA signaling complexes are most abundantly active in the cell rear during retraction [22][23][24] .…”

Comparative Study of Curvature Sensing Mediated by F-BAR and an Intrinsically Disordered Region of FBP17

“…In addition, the IDR of the cytokinetic F-BAR protein Cdc15 in fission yeast was shown to be important for the maintenance of cytokinetic ring ( Mangione et al., 2019 ). Cell protrusions and leading edge dynamics as well as cytokinesis are often simplified as actin cytoskeletal rearrangement but they are also controlled by cortical propagating waves and interlinked oscillatory networks ( Bement et al., 2015 ; Bolado-Carrancio et al., 2020 ; Katsuno et al., 2015 ; Miao et al., 2017 ; Ruthel and Banker, 1999 ; Xiao et al., 2017 ). An intriguing possibility is that kinetic parameter changes could have implications in the conversion between regimes of dynamical systems (also known as bifurcations), which then result in morphogenetic outcomes.…”

Neuropeptide Y/Y5 Receptor Pathway Stimulates Neuroblastoma Cell Motility Through RhoA Activation

“…This selective, concentration-dependent activity of the NPY/Y5R axis may be associated with tight regulation of RhoA during cell migration. To enable coordinated cytoskeleton remodeling in various sub-cellular compartments of migrating cells, RhoA activity is regulated spatially and temporally (Ridley, 2015 ; Bolado-Carrancio et al, 2020 ). While RhoA is necessary for cell movement and its insufficient activation impairs this process, the over-activation of RhoA signaling leads to stress fiber formation and inhibition of cell migration (Ridley, 2015 ).…”

“…RhoA, a small protein belonging to the Rho family of GTPases, is one of the key cytoskeleton regulators (O'connor and Chen, 2013 ). Its activity is tightly controlled in a spatiotemporal manner during cell migration (Bolado-Carrancio et al, 2020 ). In single migrating cells, RhoA is responsible for actin polymerization at the leading edge, while at the trailing edge, it controls actomyosin contractility and cell tail retraction (Narumiya et al, 2009 ; Ridley, 2015 ).…”